Regeneration is a hallmark of the peripheral nervous system (PNS) such that PNS axons are capable of both finding their original target tissues and re-establishing functional synapses with a high degree of fidelity. Following compression injury, peripheral nerves undergo a stereotyped pattern of Wallerian degeneration, characterized by myelin decompaction and phagocytosis as well as axonal die-back, which leaves intact endotubes formed by the residual basal lamina and the associated Schwann cells (reviewed in Griffin et al., 1996). The endotubes form channels into which the regenerated axons will grow. Before degeneration is complete the PNS begins the process of regeneration, which will result in complete recovery. At the onset of axonal regeneration the proximal nerve stumps form new sprouts which re-enter the endo-tubes (Bray et al., 1972; McQuarrie, 1985), and grow toward their targets. Although the basal lamina is necessary for regeneration, it is not sufficient (Hall, 1986; Ide et al., 1983). Several groups have demonstrated that Schwann cells are associated with and are required for regenerating axons to re-enter the distal stump. This is the case whether the fibers are growing into heterologous basal lamina (Feneley et al., 1991), a cellular nerve grafts (Gulati, 1988), or are sprouting into distal nerves after degeneration (Fawcett and Keynes, 1988). In addition, axons fail to regenerate across physical gaps in the absence of Schwann cells (Jenq et al., 1988; Le Beau et al., 1988; Scaravilli et al., 1986). Taken together, these data suggest that viable Schwann cells are required for axonal extension after injury, even in the permissive micro-environment of the basal lamina into which axons readily elongate.
The inventors have been interested in the transcriptional regulation of PNS development and regeneration. The transcription factor SCIP.(also known as Oct-6 and Tst-1 (He, 1991; Suzuki et al., 1990)), a member of the POU family of transcription factors, is expressed in both developing and regenerating Schwann cells. SCIP is known to regulate the myelin structural genes P0 and MBP when it is expressed by Schwann cells during a narrow window of development termed promyelination (Monuki et al., 1993; Weinstein et al., 1995). In the adult, SCIP expression is undetectable in the Schwann cell unless the nerve is injured, after which the gene is re-expressed as axons enter the distal nerve stump(Zorick, 1996). The inventors have been interested in the function of SCIP during PNS development and have recently reported on the generation of transgenic mice which express a mutant form of SCIP, termed xcex94SCIP (Weinstein et al., 1995). The transgene is under the transcriptional control of the P0 promoter, which the inventors and others have used to target expression uniquely to the Schwann cell (Lemke et al., 1988; Messing et al., 1992; Messing et al., 1994). The lines of mice the inventors have isolated and described are single copy gene transgenics which express the xcex94SCIP transgene in a Schwann cell-specific manner (Weinstein et al., 1995). The mutant SCIP protein has a deleted amino terminus, but an intact POU domain, which allows for DNA binding and POU-specific domain protein-protein interactions (Fyodorov and Deneris, 1996; Weinstein et al., 1995). Data from the study of animals that are SCIP-null suggest that SCIP function is required for the entry into and maintenance of the promyelinating phase of development (Bermingham et al., 1996; Jaegle et al., 1996; Weinstein et al., 1995). Schwann cells from animals that are null at the SCIP locus stall in their differentiation program at the onset of promyelination (Jaegle et al., 1996), and the xcex94SCIP animals which express an NH2 terminal deleted gene in mid-promyelination precociously exit this phase and enter into myelination. This early phenotypic switch results in an alteration in the 1:1 association of myelinating Schwann cells and their axons as well as an overexpression of the myelin structural genes. Based on these data the inventors have proposed a model of PNS development in which SCIP function is required for a normal promyelinating phase, during which the myelin genes are repressed, and the one-to-one relationship of myelinating Schwann cell to axon is established. The end of promyelination is marked by the down regulation of SCIP expression, high levels of myelin gene expression and the morphologic appearance of myelin around axons.
In many respects, regeneration recapitulates peripheral nerve development in that SCIP is re-expressed after peripheral nerve injury, and the myelin genes are transiently down-regulated during Wallerian degeneration. Yet, unlike promyelination, when SCIP is expressed in a tightly restricted manner, SCIP is expressed for extended periods after injury (Scherer et al., 1994). It is difficult to infer the function of this gene product during regeneration from these data, as the expression does not coincide with regenerative changes in the nerve at late stages after crush. The xcex94SCIP mice have yielded a great deal of insight into the function of and requirement for SCIP during development.
The present invention provides a method for regenerating nervous tissue comprising contacting the tissue with an effective amount of Schwann cells expressing xcex94SCIP to regenerate the nervous tissue.
The present invention also provides a method for treating a subject in need of nervous tissue regeneration comprising introducing an effective amount of Schwann cells expressing xcex94SCIP into the subject to induce nervous tissue regeneration in the subject. The subject in need of nervous tissue regeneration may have a neurodegenerative disease or damaged neurons.
Further provided by the present invention is a method of inducing nervous tissue regeneration in a subject in need of such treatment comprising administering to the subject an effective amount of xcex94SCIP to induce nervous tissue regeneration in the subject. The administration of xcex94SCIP may be effected by administration of the xcex94SCIP protein or the xcex94SCIP nucleic acid.